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Biomedical subjects

J R Walters

Publications and source records attributed to J R Walters.

At least 145 records · Page 8Linked to original sources
PubMed1976

Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors.

An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.

4-Butyrolactone↗
PubMed1976

Effect of anesthetic doses of gamma-hydroxybutyrate on the acetylcholine content of rat brain.

Gamma-hydroxybutyrate administered in anesthetic doses produces a time dependent increase in the levels of rat barin acetylcholine. A maximal increase in whole brain and subcortical levels of acetylcholine is observed about 15 min after administration of the lactone form of the drug. A similar GHB-induced increase in acetylcholine is observed in the striatum and a 75% increase in the hippocampus 15 min after administration of the drug. A good temporal correlation was not obtained between the increase in acetylcholine and the depth of anesthesia produced by the drug. Gamma-hydroxybutyrate did not cause a significant change in the striatal or hippocampal levels of choline. Possible mechanisms involved in the production of this increase in acetylcholine are discussed.

4-Butyrolactone↗
PubMed1976

Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid.

Stimulation of the nigro-neostriatal or mesolimbic dopamine pathway results in a stimulus dependent increase in the accumulation of dihydroxyphenylacetic acid (DOPAC) in the neostriatum and olfactory tubercles, respectively. A block of impulse flow induced pharamacologically by administration of gamma-butyrolactone or by placement of a lesion in the dopamine pathway results in a decrease in the steady state levels of DOPAC. Drugs which have previously been shown to alter impulse flow in central dopaminergic neurons also produce a predictable change in the brain levels of DOPAC. Drugs which increase impulse flow in nigro-neostriatal or mesolimbic dopamine neurons increase DOPAC levels in the striatum and olfactory tubercles and drugs which reduce impulse flow cause a reduction in DOPAC. Pargyline, a monoamine oxidase inhibitor, causes a rapid depletion of striatal DOPAC suggesting that this metabolite is rapidly cleared from the brain. Administration of benztropine, a potent inhibitor of dopamine reuptake, causes a significant decrease in striatal DOPAC and partially prevents the stimulus-induced increase in the accumulation of DOPAC. These observations together with the finding that about 85% of the DOPAC in the striatum disappears when the dopamine neurons in the nigro-neostriatal pathway are destroyed suggests that the majority of striatal DOPAC is formed within the dopaminergic neurons and may reflect the metabolism of dopamine which has been released and recaptured. We conclude that short-term changes in brain levels of DOPAC appear to provide a useful index of alterations in the functional activity of central dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

D & L amphetamine stereoisomers: comparative potencies in affecting the firing of central dopaminergic and noradrenergic neurons.

The effect of the d- and l-isomers of amphetamine on the activity of dopaminergic neurons in the substantia nigra zona compacta and noradrenergic neurons in the locus coeruleus was studied in anesthetized and gallamine paralyzed rats using single unit recording techniques. d- and l-Amphetamine administered intravenously were equally effective in depressing the activity of locus coeruleus cells. However, although d-amphetamine was a potent inhibitor of substantia nigra dopamine containing cells, l-amphetamine was ineffective in causing more than a 45% inhibition of over half of the DA cells studied, even when given in nearly lethal doses. In the remaining dopamine neurons l-amphetamine was only 0.2 to 0.05 times as potent as d-amphetamine in producing both 50 and 100% inhibition of firing rate. These findings, when combined with recent biochemical studies by other authors, suggest that l-amphetamine, at low doses, has a preferential effect on noradrenergic as compared to dopaminergic neurons. The consequences of these findings for the interpretation of studies in which d- and l-amphetamine have been used as pharmacological tools to determine the catecholamine system responsible for a particular behavior in man and animals is discussed.

Amphetamine↗
PubMed1975

Piribedil and apomorphine: pre- and postsynaptic effects on dopamine synthesis and neuronal activity.

Piribedil and apomorphine can cause a complete but temporary inhibition in firing of the DA-containing neurons. The cells recover to approximately 30 to 40% of the original firing rate, and with subsequent administration of the drug become more and more resistant to further inhibition. At this point they are also resistant to inhibition by other direct- or indirect-acting DA agonists that are normally able to inhibit the firing of DA cells. This effect may be due to an interaction of the DA agonists with the postsynaptic DA receptors, but apomorphine at least is able to inhibit the firing of DA cells directly when iontophoresed onto the DA cell body (Aghajanian and Bunney, 1973). These drugs can block the increase in DA synthesis observed in the absence of impulse flow, indicating a presynaptic site of acttion. Taken together, these results suggest that in interpreting the effects of drugs interacting with the DA systems several points of interaction should be considered.

Animals↗